Researchers studying ageing in mice found that declining cellular recycling helps 'zombie cells' evade immune clearance; restoring the process improved their removal and reduced age-related inflammation

Researchers studying ageing in mice have identified a cellular process that may help explain why what are called 'zombie cells' become harder for the body to remove as it gets older. The new study led by researchers at Albert Einstein College of Medicine and published in Nature Aging, found that a decline in a cellular recycling system affects both these damaged cells and the immune cells responsible for clearing them.The cells, formally known as senescent cells, are living cells that have stopped dividing or functioning normally but remain in tissues. Their accumulation has been linked to chronic inflammation and age-related diseases.During the study, researchers focused on chaperone-mediated autophagy, or CMA, a cellular recycling process that identifies damaged or unnecessary proteins and breaks them down. CMA uses specialised 'chaperone' molecules to target proteins for digestion. Previous research led by Ana Maria Cuervo had found that CMA activity declines with age and that reduced activity can allow unwanted cellular material to accumulate.The latest experiments, conducted mainly in mice, found that this age-related decline in CMA affects senescent cells as well as macrophages, immune cells that help remove them. Analyses of human lung tissue were also carried out to examine whether the findings could have relevance to humans.'Zombie cells' are not always harmfulSenescent cells are useful in wound healing. Some injured cells enter a senescent state and release substances that recruit other cells needed for tissue repair.Once their job is complete, these senescent cells are normally removed by macrophages. These immune cells perform several functions, including fighting infections, clearing dead cells and helping regulate inflammation and tissue repair.Researchers tested what happens when CMA is absent from macrophages. They used mice whose macrophages had been genetically altered to lack the recycling process. Compared with control mice, these animals accumulated more senescent cells at wound sites and their wounds healed more slowly.The results indicated that CMA activity inside macrophages is important for their ability to clear senescent cells during tissue repair.Changes as cells get olderThe researchers then examined what happens when cells themselves become senescent. Scientists can produce senescent cells in laboratory experiments by exposing normal body cells to drugs that stop them from dividing.The team used fibroblasts, cells found in connective tissue, taken from young and old mice. When fibroblasts from young mice became senescent, they increased their CMA activity. Cells taken from old mice responded differently. Their CMA activity was already low and failed to increase after the cells became senescent.That difference affected how the cells handled unwanted proteins. Certain proteins inside senescent cells from older animals were not properly broken down through CMA.As a result, the cells released undigested toxic substances. These secretions made nearby healthy cells more likely to become senescent and also interfered with macrophages' ability to recognise and clear the existing senescent cells.The problem was occurring on both sides of the process. Macrophages from older animals also had lower CMA activity than those from younger animals, reducing their ability to engulf and remove senescent cells.Testing CMA activatorScientists have been developing drugs known as senolytics that are designed to eliminate senescent cells. However, the new findings suggest that experiments involving young cells that are artificially made senescent may not fully reproduce what happens inside an ageing body.The researchers instead investigated whether increasing CMA activity could improve the body's existing system for clearing these cells. They tested CA77.1, a small-molecule CMA activator that the researchers had previously developed.Aged mice were given CA77.1 orally every day for five months. The treatment reduced the accumulation of senescent cells in several organs and also reduced signs of inflammation and fibrosis.In another experiment, researchers treated macrophages taken from aged mice with CA77.1. The treatment restored their ability to engulf particles to levels comparable with macrophages taken from young mice.Possible link to lung fibrosisThe researchers also examined idiopathic pulmonary fibrosis, or IPF, an age-associated disease in which scar tissue progressively builds up in the lungs and makes breathing increasingly difficult.When the team examined lung samples from patients with IPF, they found markedly reduced CMA activity. This raised the possibility that increasing CMA activity could have an effect on lung fibrosis.The researchers then tested CA77.1 in a mouse model of the disease. When treatment began early after lung injury, the mice showed less severe lung fibrosis as well as reduced signs of cellular senescence and inflammation.The findings do not establish CA77.1 as a treatment for people. The researchers said further work is needed to determine whether the approach can eventually be developed safely for human age-related diseases.“Our research connects two major drivers of aging- declining CMA and cellular senescence, and shows for the first time how their interaction allows senescent cells to evade clearance by the immune system in old organisms,” Cuervo said.“We’ve also found that instead of trying to kill zombie cells, we may be able to restore their interaction with the immune system so that the body can clear them naturally. The next challenge is determining whether this approach can eventually be developed into a safe treatment for age-related diseases in people,” Cuervo concluded.